NO135590B - - Google Patents

Description

The invention relates to analogical method to

production of pyridine derivatives with antidepressant action.

The antidepressants that have gained the most widespread clinical use are the tricyclic tertiary amines imipramine, with structural formula: and amitriptyline, with structural formula:

Secondary amines such as desipramine with structural formula:

and nortriptyline with structural formula: is used to a somewhat lesser extent. However, all these substances do not have desirable side effects when used therapeutically, such as orthostatism, anticholinergic effects, and above all an arrhythmogenic cardiac arrhythmia-inducing effect when administered in higher doses to elderly patients. The secondary amines such as desipramine and nortriptyline also have the known effect of inducing anxiety in many depressed patients. In addition, all of the aforementioned substances have the disadvantage that the antidepressant effect only occurs after a few weeks of treatment. This late-onset effect must be attributed to the fact that all the drugs have a low antidepressant activity. It is also known from the literature that certain 1,1-diphenyl-3-aminopropenes such as compounds with the formula: have an antidepressant effect, see J. Med. Chem. 14 161-164 (1971). In the literature, further compounds with the formula: where X is chlorine or bromine and where R is hydrogen or methyl, have been described as having antihistamine effect and antidepressant effect, see US patent no. 3,423-510. The compound with formula VI where Y is Br and R is methyl is designated brompheniramine in table 1 below. However, both the compounds exemplified by compound V above, as well as the compounds exemplified by compound VI above, have the serious side effect of being anxiolytic and also orthostatic inducing.

A main purpose of the present invention is to provide an analogue method for the production of new compounds with a good antidepressant effect. A further object of the invention is to provide an analogue method for the preparation of compounds with an antidepressant effect which does not give rise to orthostatism, anticlinergic effects or arrhythmogenic effects.

The invention relates to analogue methods for the production of active compounds with the formula:

where the pyridine nucleus is bound in the 2-, 3- or ^-position to the adjacent carbon atom and where the substituents R<1> means Br and R means H or Br and therapeutically acceptable acid addition salts thereof, which in contrast to the most clinically used tricyclic substances such as imipramine, desipramine, amitriptyline and nortriptyline, as well as - in contrast to the compounds known from the literature, such as the compounds with formula V and VI" are powerful antidepressants, depression-relieving agents, which do not cause the most troublesome side effects such as anxiety, orthostatism and cardiac arrhythmias.

The preferred compounds according to the invention are the compounds

3-(4'-bromophenyl)-3-(3"-pyridyl)-dimethylallylamine, 3-(41-bromophenyl)-3-(k"-pyridyl)-dimethylallylamine and (Z)-3-(4'-bromophenyl) )-3-(2"-pyridyl)-dimethylallylamine.

The compounds can be prepared according to the invention by dehydrating a compound with the formula:

to form a compound with the formula: The dehydration of the compound with formula IX can be carried out, for example, by means of concentrated sulfuric acid and heating the reaction mixture to a high temperature, around 165 - 175°C. The dehydration of the compound of formula IX can also be carried out with other types of acid catalysis such as, for example, using hydrochloric acid, HC1, phosphoric acid, H^PO^, potassium hydrogen sulphate, KHSO^ or oxalic acid (COOH^. Other methods for dehydrating the compound of formula IX for the formation of a compound of formula X, is dehydration using <1>phosphorus oxychloride, POCl^,in -pyridine as well as dehydration with 1thionyl chloride, SOC12, in pyridine. Catalytic dehydration of the compound of formula IX can also be used. The dehydration is carried out in in this case at a temperature of around 300 - 500°C with a catalyst such as kaolin, aluminum or aluminum oxide as A^O^ as catalyst.

The starting materials of formula IX can be prepared in an optional way, for example by reaction between a compound of formula: with a pyridyl-lithium compound of formula:

1 2

in which formulas R and R have the above meaning and the lithium atom is bound in the ortho, meta or para position on the pyridine nucleus.

The final compound produced according to the invention can exist in cis- and trans-form or E- and Z-form according to IUPAC nomenclature, and the therapeutic effect cannot be unequivocally attributed to just one of these forms, but can be attributed to a greater or lesser extent one or both of the cis forms and the .trans forms .

In clinical use, the compound according to the invention is normally administered orally, rectally or by injection in the form of pharmaceutical preparations containing the active ingredient in the form of a free base or a pharmaceutically acceptable salt thereof, such as e.g. the hydrochloride, lactate, acetate, oxalate or the like together with a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or a digestible capsule.

Suitable daily doses of compounds according to the invention for therapeutic treatment are 5 - 500 mg by oral administration, preferably 50 - 250 mg and 1 - 100 mg by parenteral administration, preferably 10 - 50 mg.

Biological effect.

It is not possible to experimentally induce depression in laboratory animals. In order to assess a possible antidepressant effect in new substances, biochemical and pharmacological test methods must therefore be resorted to. Such a test method which seems to give such results in an association's antidepressant effect which agrees well with the clinically mentioned effect, has been prepared and described in European Journal of Pharmacology 5, 367 - 373 (1969) and European Journal of Pharmacology 5j 357 - 366 (1969). This test method involves the ability of a compound to block the release of norepinephrine in the brain and heart which is induced by an injection of 4,α-dimethyl-m-tyramine, as well as the ability of the compound to block the release of 5-hydroxy-tryptamine in the brain which is induced by an injection of 4-methyl-a-ethyl-m-tyramine is tested. Substances that block the release of noradrenaline in the brain and heart are above all secondary amines: of the type desipramine and nortriptyline, which have the serious side effect and lead to anxiety. The blockade of norepinephrine release in the brain and heart caused by these compounds probably also induces orthostatism. The real anti-depressant effect of a drug seems to be associated with a blockade of 5-hydroxy-tryptamine release. As shown below, it has surprisingly been found that the compound produced according to the invention has a strong blocking effect and the release of 5-hydroxy-tryptamine induced by 4-methyl-o-ethyl-m-tyramine, while the ability of the compounds to block the the release of norepinephrine induced by 4-α-dimethyl-m-tyramine is completely absent or is very weak. Moreover, the compound produced according to the invention differs from all hitherto used tricyclic antidepressants in that they have a very low cardiac arrhythmia-inducing effect than previously used tricyclic agents. Compounds of the type discussed in Journal of Medicinal Chemistry 14, l6l - 164

(1971) does indeed have an antidepressant effect, but this antidepressant effect is low compared to the effect of the compound produced according to the invention and these known compounds, which are illustrated by compound V above, also have a significant ability to block 4-α-dimethyl-m- tyramine-induced norepinephrine release in the brain and heart, which in humans leads to the aforementioned unwanted side effects anxiety and probably also leads to orthostatism. The compounds mentioned in US patent no. 3.42:3.510 and illustrated by compound VI above are referred to as antihistamines and antidepressants. The compound brompheniramine of formula: does indeed appear to have a strong blocking effect on 5-hydroxy-tryptamine release, but this compound also strongly blocks 4-a-dimethyl-m-tyramine-induced norepinephrine release, which in humans leads to unwanted side effects such as anxiety and orthostatism. A pharmacological comparison between the compound according to the invention and previously used tricyclic antidepressants as well as compounds mentioned in the literature is given below. 1. Blocking effect on 4-methyl-arethyl-m-tyramine-induced 5-hydroxytryptamine release.

1. 1 Rats

The substance to be tested is injected intraperitoneally into a rat. 30 minutes later, 50 mg/kg 4-methyl-α-ethyl-m-tyramine is injected intraperitoneally. Two hours later, the animals are killed and the amount of 5-hydroxytryptamine in the brain is determined. Animals treated only with the test substance, respectively only with 4-methyl-α-ethyl-m-tyramine, as well as untreated animals serve as controls. The percentage inhibition of 5-hydroxytryptamine release is determined according to the following formula:

A = amount (ng/g) of 5-hydroxytryptamine in brain after administration of test substance and 4-methyl-a-ethyl-m-tyramine.

B = amount (ng/g) of 5-hydroxytryptamine in brain after administration of 4-methyl-α-ethyl-m-tyramine.

C = amount (ng/g) of 5-hydroxytryptamine in brain after administration of test substance.

The effective dose that inhibits 5-hydroxytryptamine release to 50$ (ED^q) is then calculated by regression analysis. The test results are set out in Table 1 below.

1. 2 Mouse

The substance to be tested is injected intraperitoneally into mice. 30 minutes later, 100 mg/kg 4-methyl-α-m-tyramine is injected intraperitoneally. 90 minutes later the test substance is administered again, now in an amount corresponding to half of the original dose and 30 minutes later 4-methyl-α-ethyl-m-tyramine (100 mg/kg) is administered. A further 2 hours later, the animals are killed and the amount of 5-hydroxytryptamine in the brain is determined. Percentage inhibition of 5-hydroxytryptamine release and ED^g is determined in the same way as under 1.1. An elaborate method is described in the European Journal of Pharmacology 5, 357-366 (1969). The test results are set out in Table 1 below. 2. Blocking effect on 4,α-dimethyl-m-tyramine-induced norepinephrine release.

The substance to be tested is injected intraperitoneally into mice (10 mg/kg). 30 minutes later, 4,α-dimethyl-m-tyramine (12.5 mg/kg) is administered. 90 minutes later half of the original dose of test substance (5 mg/kg) is administered to the animals and 30 minutes later 4,α-dimethyl-m-tyramine (12.5 mg/kg) is administered. A further 2 hours later, the animals are euthanized and the amount of norepinephrine in the brain and heart is determined. Animals treated only with test substance or only with 4,ct-dimethyl-m-tyramine, as well as untreated animals, are used as controls.

Percentage inhibition of norepinephrine release is determined according to the following formula:

A = amount (ng/g) of norepinephrine in brain, respectively heart after

administration of test substance and 4,α-dimethyl-m-tyramine.

B = amount (ng/g) of norepinephrine in brain, respectively heart after

administration of 4,0-dimethyl-m-tyramine.

C = quantity (ng/g) of norepinephrine in the brain or heart after administration of the test substance.

The test results are set out in Table 1 below.

3. Cardiac arrhythmia-causing effect.

A solution of the test substance is slowly infused into nembutal-anesthetized rats and the animals' electrocardiogram is observed. After a certain time, an irregular heartbeat occurs which becomes more severe and eventually leads to ventricular fibrillation, whereby the animals die. The cumulative dose required to induce ventricular fibrillation is given in Table 1 below.

As can be seen from the test values in Table 1, compared to the reference substances, the tested compounds according to the invention have a strong blocking effect on the 5-hydroxytryptamine-releasing effect of 4-methyl-α-ethyl-m-tyramine, while the effect of the compound according to the invention of the 4,α-dimethyl-m-tyramine-induced norepinephrine release is low. The dose in mg/kg body weight i.p. which induces ventricular fibrillation by constant infusion is likewise significantly lower in the tested compounds according to the invention, compared to the reference substances, which means that the compound according to the invention has a significantly lower cardiac arrhythmia-inducing effect than the reference substances.

Production of the compound according to the invention is illustrated with the following examples.

Example 1.

Preparation of (E)- and (Z)-3~(4'-bromophenyl-3-(2"-pyridyl)-dimethylallylaminodihydrochloride.

97 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(2"-pyridyl)-propanol are dissolved in 300 ml of 85$ H^SO^ and heated at 170°C for 10 minutes The reaction mixture is then poured into 1 liter of water, made alkaline with 10 N NaOH and extracted with 2 x 250 ml of ether which is dried, treated with activated charcoal and evaporated in. The product formed is dissolved in 250 ml of ether and dry HCl is introduced. The precipitate formed is filtered off and recrystallized from ethanol (99.5$). Yield 40 g (Z(-3-(4'-bromophenyl)-3~(2"-pyridyl)-dimethyl-allylamine dihydrochloride. Melting point 195°C .

The mother liquor from the recrystallization is evaporated, the residue is dissolved in acetone. After 24 hours, the precipitate formed therein is filtered off. Yield 15 g of (E)-3-(4'-bromophenyl)-3-(2"-pyridyl)-dimethylallylamine dihydrochloride. Melting point 160°C.

Production of the starting material.

1-(4'-Bromophenyl)-3-(N,N-dimethylamino)-1-(2"-pyridyl)-propanol was prepared as follows:

To 50 g of n-butyllithium in 0.5 1 of dry ether was added

-40°C put 23.7 g of 2-bromopyridine as quickly as possible without that. the temperature increases. After the addition is complete, the mixture is stirred

another 30 minutes. 1.5 liters of dry ether are then added and then 197 g of io-dimethylamino-4'-bromopropionphenone so that the temperature does not exceed -40°C. The cooling is interrupted and the mixture is stirred overnight, after which the reaction mixture is poured onto ice and diluted HCl, which is then washed with a little methylene dichloride. The water phase is then made alkaline and extracted with ether, which is dried and evaporated. The residue is recrystallized from petroleum ether at 40-60°C. Yield 98 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(2"-pyridyl)-propanol. Melting point 85°C. Example 2.

Preparation of 3-(4'-bromophenyl)-3-(3"-pyridyl)-dimethylallylamine dihydrochloride.

3.6 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3"-pyridyl)-propanol are dissolved in 15 ml of 85$ I^SO^ and heated at 170°C in 10 minutes. The reaction mixture is poured into 60 ml of water which is then made alkaline with 10 N NaOH, extracted with 2 x 25 ml of ether. The ether is dried with Na2SOil, treated with activated carbon

and evaporates. The residue is dissolved in 25 ml of acetone and an equivalent amount of oxalic acid dissolved in 25 ml of acetone is added. The formed precipitate is filtered off, dissolved in 50 ml of water and made basic with 10 N NaOH and extracted with 2 x 25 ml of ether. The ether solution

dried with NagSO^, filtered, after which dry HC1 is introduced. The formed precipitate is filtered. Yield 1.2 g of 3-(4<*->bromophenyl)-3-(3"-pyridyl)-dimethylallylamine dihydrochloride. Melting point 193°C. Preparation of the starting material.

1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3"-pyridyl)-propanol is prepared in the following way: To 9 g of n-butyllithium in 200 ml of dry ether is added by

-40°C 20 g of 3-bromopyridine as quickly as possible without increasing the temperature. After the addition is complete, stir the mixture further

for 30 minutes. 32.5 g of io-dimethylamino-4'-bromo-propiophenone are then added so that the temperature does not exceed -40°C. The cooling is interrupted and the mixture is stirred overnight, after which the reaction mixture is poured onto ice and diluted HCl, which is washed with ether and extracted with methylene dichloride. The methylene chloride is dried and evaporated. The crystals are dissolved in water which is then made alkaline with Na2CO^ solution, extracted with ether, dried and evaporated and recrystallized from isopropyl ether, petroleum ether 1:1. Yield 4 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3"-pyridyl)-propanol. Melting point 67°C.

Example 3-

Preparation of 3-(4'-bromophenyl)-3-(4"-pyridyl)-domethylallylamine dihydrochloride. 3 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-( 4"-pyridyl)-propanol is dissolved in 10 ml of 85% H 2 SO 4 and heated at 170°C for 15 minutes. The reaction mixture is then poured into ice water which is made alkaline with 10 N NaOH and extracted with ether. The ether phase is dried and dry HCl is introduced. The formed precipitate is filtered off ... and recrystallized by dissolving it in ethanol and separating it by adding acetone. Yield 1.4 g 3~(4'-bromophenyl)-3~(4"-pyridyl)-dimethylallylamine dihydrochloride. Melting point 190°C. Preparation of the starting material. 1-(4'-bromophenyl)-3L(N,N -dimethylamino)-1-(4"-pyridyl)-propanol, is prepared as follows: To 10 g of n-butyllithium in 250 ml of dry ether is added by

-40°C 17.7 g of 4-brorapyridine as quickly as possible without the temperature rising, after which the mixture is further stirred for 30 minutes. 28.7 g of dimethylamino-4'-bromopropiophenone are added so that the temperature does not exceed -40°C. The cooling is stopped and the mixture is stirred overnight, after which the reaction mixture is poured onto ice and diluted HC1. The water phase is washed with methylene

dichloride after which it is made alkaline with 10 N NaOH and extracted with ether. The ether phase is dried with Na2S0|j, cooled and evaporated. The residue is recrystallized from diisopropyl ether. Yield 3 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(V'-pyridyl)-propanol. Melting point 120°C

Example 4.

Analogously to examples 1-3, 3-(3's4'-dibromophenyl)-3-(2"-pyridyl)-dimethylallylamine hydrochloride is prepared. Melting point 136°C.

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds of the formula as well as therapeutically tolerable acid addition salts thereof, where the pyridine ring is bound in the 2-, 3- or 4-position to the adjacent carbon atom and where R means Br and R means H or Br, characterized in that a compound with the formula is dehydrated to form a compound of the formula I, after which the thus formed compound, if desired, is transferred to a therapeutically tolerable acid addition salt by reaction with a suitable acid, or that the Z-form and the E-form of the formed compound of the formula I are isolated. 2. Method according to claim 1 for the production of a compound of formula or therapeutically tolerable acid addition salts thereof, characterized in that a compound of formula is dehydrated and, if desired, the compound formed is transferred to a therapeutically tolerable acid addition salt by reaction with a suitable acid, or that the Z form and the E form of the compound of formula I formed are isolated.